We operate three clinical centers of the Diabetes Prevention Program (DPP), a multicenter randomized clinical trial of diabetes prevention in high-risk, but nondiabetic, adults. Nationally, the DPP enrolled 3,234 volunteers who received standard lifestyle recommendations and were randomly assigned to one of three interventions: intensive lifestyle with the aim of losing and maintaining 7% weight loss and achieving > 150 minutes per week of moderate intensity physical activity, metformin therapy with 850 mg twice per day, or placebo. The development of diabetes in the lifestyle intervention and metformin-treated groups were reduced by 58% and 31%, respectively, compared with the placebo group, during the first three years of treatment and follow-up. Many important issues remained unanswered, however. Specifically, whether the decrease in the development of diabetes can be sustained is unknown. Moreover, determining whether the delay or prevention of diabetes will translate into a decrease in retinopathy, nephropathy, neuropathy, and cardiovascular disease, all of which require more years to develop than the DPP period of study, is critical to establish the true impact of the DPP on public health. This long-term follow-up study of the DPP, the DPPOS, addresses these issues. Several findings were reported this fiscal year. Individual risk estimates. Both lifestyle and metformin interventions can delay or prevent progression to type 2 diabetes mellitus (DM) in people with impaired glucose regulation, but there is considerable interindividual variation in the likelihood of receiving benefit. Understanding an individuals 3-year risk of progressing to DM and regressing to normal glucose regulation (NGR) might facilitate benefit-based tailored treatment. We used the values of 19 clinical variables measured at the Diabetes Prevention Program (DPP) baseline evaluation and Cox proportional hazards models to assess the 3-year risk of progression to DM and regression to NGR separately for DPP lifestyle, metformin, and placebo participants who were adherent to the interventions. Unlike our previous analyses that sought to explain population risk, these analyses evaluate individual risk. The models can be used by overweight and obese adults with fasting hyperglycemia and impaired glucose tolerance to facilitate personalized decision-making by allowing them to explicitly weigh the benefits and feasibility of the lifestyle and metformin interventions.(3) Depression and anti-inflammatory markers. Antidepressant medication use (ADM) predicts type 2 diabetes (T2DM). This paper assessed the role of inflammatory markers in this relationship within the Diabetes Prevention Program (DPP). ADM was significantly associated with elevated CRP and incident T2DM. In the PLB group, ADM and CRP independently predicted onset of T2DM, however CRP did not significantly mediate the effect of ADM.(2) Additional risk factors for diabetes and microvascular complications. Approximately half of the participants in the Diabetes Prevention Outcomes Study (DPPOS) had diabetes after 15 years of follow-up, whereas nearly all the others remained with pre-diabetes. We examined whether formerly unexplored factors in the DPPOS coexisted with known risk factors that posed additional risk for, or protection from, diabetes as well as microvascular disease. In prediction models adjusted for demographics and known diabetes risk factors, two formerly unknown factors were associated with risk for both diabetes and microvascular disease -- number of medications taken and variability in HbA1c. Total comorbidities increased risk for diabetes, whereas higher blood pressure and the use of anti-hypertensive drugs were associated with increased risk of microvascular disease.(7) Dietary macronutrients and weight loss. We evaluated the associations between diet and weight at baseline and to identify specific dietary factors that predicted weight loss among DPP participants. Diet was assessed by a food frequency questionnaire. Higher carbohydrate consumption among DPP participants, specifically high-fiber carbohydrates, and lower total and saturated fat intake best predicted weight loss when adjusted for changes in calorie intake. Our results support the benefits of a high-carbohydrate, high-fiber, low-fat diet in the context of overall calorie reduction leading to weight loss, which may prevent diabetes in high-risk individuals.(8) A multicenter study of genetic susceptibility to type 2 diabetes. To identify common or rare genetic variation with potential therapeutic implications for T2D, we analyzed and replicated genome-wide protein coding variation in a total of 8,227 individuals with T2D and 12,966 individuals without T2D of Latino descent. We identified a novel genetic variant in the IGF2 gene associated with 20% reduced risk for T2D.(6) Other prevention activities. Based on experience with this project, the principal investigator was asked to edit and write chapters on prevention of type 2 diabetes.(1, 4, 5) Most studies reviewed in these writings showed that type 2 diabetes can be prevented or delayed to varying extents by a variety of drugs used to treat type 2 diabetes and by lifestyle interventions. Whether these interventions affect only hyperglycemia during the time the interventions are provided or also affect other health outcomes, such as mortality rates and the development of diabetes complications, is largely unknown.